Investigating the Role of E3 Ubiquitin Ligases in Flavivirus Infection

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Flaviviruses such as Dengue (DENV) and Zika (ZIKV) pose serious public health challenges, infecting over 400 million people a year globally. Despite this, no effective vaccines or antivirals are currently available to combat flaviviruses, highlighting the need to improve our understanding of their biology. While it is known that flaviviruses hijack the host ubiquitylation system to their advantage, E3-ligases that catalyse ubiquitylation have received limited attention on their role in the flavivirus lifecycle, with limited understanding of normal E3-ligase biology. This project aims to identify and characterise E3-ligases of the host cell that are co-opted to have a proviral effect on the flavivirus lifecycle. We will apply both an unbiased as well as a candidate-based approach to identify E3-ligases with altered activity in ZIKV infection. We will combine genetic, biochemical and proteomics strategies to perform detailed characterization of these E3- ligases in virus replication. Finally, we aim to verify the conservation of these E3-ligase-mediated processes in the mosquito vector to define universal infection mechanisms in both human and the vector host. The insights gained from this study will further our understanding of; healthy E3-ligase biology and immune function in humans, flavivirus biology, and potentially contribute to the development of broad-spectrum antivirals.BBSRC Relevant Areas This work comes under the wider BBSRC theme of 'Bioscience for an integrated understanding of health', specifically the priority areas 'Healthy ageing across the life course' and 'Lifelong health and wellbeing'. We will gain an understanding of the fundamental aspects of E3-ligase cellular function, with flavivirus infection allowing us to identify key interactions and activities of E3-ligases which are crucial to modulating wider cellular biology. Identifying E3-ligases with conserved functions across different flavivirus species and in different host species will also allow us to identify core E3-ligases which are key in cellular processes such as metabolism and the immune response. Together, this will improve our understanding of cellular biology and also identify key E3-ligases which are important in healthy function of the cell and particularly susceptible to dysfunction in disease.